The present invention, in some embodiments thereof, relates to a method of reducing toxicity of bacteria and more particularly reducing antibiotic resistance in bacteria.
Bacteria have evolved to overcome a wide range of antibiotics, and resistance mechanisms against most of the conventional antibiotics have been identified in some bacteria. Accelerated development of newer antibiotics is being overrun by the pace of bacterial resistance. In the USA, for example, over 70% of hospital-acquired infections involve bacteria resistant to at least one antibiotic, and in Japan over 50% of the clinical isolates of Staphylococcus aureus are multidrug-resistant.
This increasing threat has revived research into phage therapy. For example, a clinical phase I and II control trial was recently completed successfully for the treatment of chronic bacterial ear infections. Nevertheless, although phage therapy has been practiced for several decades in some of the former Soviet Union countries and Poland, there are still many doubts as to its ability to replace antibiotics. Major concerns over the use of phage therapy include neutralization of phages by the spleen/liver and by the immune system, their narrow host range, bacterial resistance to the phage, and lack of sufficient pharmacokinetic and efficacy studies in humans and animals.
A recent study used phages as a genetic tool to increase bacterial susceptibility to antibiotics. That study used phage M13, of the Gram-negative Escherichia coli, to genetically target several gene networks, thus rendering the bacteria more sensitive to antibiotics (10). It demonstrated that disrupting the SOS response by M13-mediated gene-targeting renders the bacteria several-fold more sensitive to a variety of antibiotics. It also demonstrated that phage-mediated gene transfer combined with antibiotics increases the survival of mice infected with pathogenic E. coli. Overall, the study showed that transferring genes by phage M13 weakens the bacteria, and render them more susceptible to killing by antibiotics. The end result is very similar to conventional phage-therapy practices, in which phages are used to directly kill the pathogen.
Different approaches make use of phages as “disinfectants” of pathogens present on edible foods, plants, and farm animals. In addition to increasing the shelf life of these products, the treatment is intended to prevent occasional outbreaks of disease. The US Food and Drug Administration recently approved the use of an anti-Listeria phage cocktail for application on meat and poultry as a preventive measure to against Listeria (5). Other phage cocktails have been approved as food additives in Europe, and many are currently being developed by phage biotech companies. These applications demonstrate that phages can be dispersed in the environment and efficiently target pathogens in their surroundings.
Pathogen resistance to antibiotics is a rapidly growing problem, leading to an urgent need for novel antimicrobial agents. Unfortunately, development of new antibiotics faces numerous obstacles, and a method that will resensitize pathogens to approved antibiotics therefore holds key advantages.
Lu and Collins [Proc Natl Acad Sci USA. 2009 Mar. 24; 106 (12):4629-34] teach genetically modified bacteriophage which serve to weaken bacteria such that they are more susceptible to antibiotics.
Hagens and Blassi [Lett Appl Microbiol. 2003; 37 (4):318-23] teach genetically modified filamentous phage as bactericidal agents.
Other background art includes U.S. Patent Application No. 20100322903 and Lederberg J., 1951, J Bacteriol 61:549-550 which teaches that wt rpsL is a dominant sensitive allele with regard to streptomycin resistance.